Direct Amination of Alcohols Catalyzed by Aluminum Triflate: An Experimental and Computational Study

Article abstract of DOI:10.1002/chem.201801492

Among the best-performing homogeneous catalysts for the direct amination of activated secondary alcohols with electron-poor amine derivatives, metal triflates, such as aluminum triflate, Al(OTf)₃, stand out. Herein we report the extension of this reaction to electron-rich amines and activated primary alcohols. We provide detailed insight into the structure and reactivity of the catalyst under working conditions in both nitromethane and toluene solvent, through experiment (cyclic voltammetry, conductimetry, NMR spectroscopy), and density functional theory (DFT) simulations. Competition between aniline and benzyl alcohol for Al in the two solvents explains the different reactivities. The catalyst structures predicted from the DFT calculations were validated by the experiments. Whereas a S_N1-type mechanism was found to be active in nitromethane, we propose a S_N2 mechanism in toluene to rationalize the much higher selectivity observed when using this solvent. Also, unlike what is commonly assumed in homogeneous catalysis, we show that different active species may be active instead of only one.

Full text of DOI:10.1002/chem.201801492

A Journal of
Accepted Article
Title: Direct Amination of Alcohols Catalyzed by Aluminum Triflate: an
Experimental and Computational Study
Authors: Pierre-Adrien Payard, Qingyi Gu, Wenping Guo, Qianran
Wang, Matthieu Corbet, Carine Michel, Philippe Sautet,
Laurence Grimaud, Raphael Wischert, and Marc Pera-Titus
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to ensure accuracy of information. The authors are responsible for the
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To be cited as: Chem. Eur. J. 10.1002/chem.201801492
Link to VoR: http://dx.doi.org/10.1002/chem.201801492
Supported by

Chemistry - A European Journal
10.1002/chem.201801492
FULL PAPER
Direct Amination of Alcohols Catalyzed by Aluminum Triflate: an
Experimental and Computational Study
[
a,b]
[a]
[a,c]
[a]
[a]
Pierre-Adrien Payard,
Qingyi Gu, Wenping Guo,
Qianran Wang, Matthieu Corbet, Carine
[c]
[c,d]
[b]
[a]
[a]
Michel, Philippe Sautet, Laurence Grimaud, Raphael Wischert, * and Marc Pera-Titus *
[
2]
Abstract: Among the best performing homogeneous catalysts for
the direct amination of activated secondary alcohols using electron-
poor amine derivatives, metal triflates, such as aluminum triflate,
is generated as sole byproduct. Unlike traditional pre-activation
methods which require transformation of the OH-group into
leaving groups such as halides, carboxylates, phosphates or
carbonates, this synthetic approach is consistent with the
principles of green chemistry, both in terms of atom economy
3
Al(OTf) , stand out. Here we report the extension of this reaction to
electron-rich amines and activated primary alcohols, and provide
detailed insight into the structure and reactivity of the catalyst under
working conditions in both nitromethane and toluene solvent,
through experiment (cyclic voltammetry, conductimetry, NMR), and
density functional theory (DFT) simulations. Competition between
aniline and benzyl alcohol is found to be critical for explaining how
the solvent conditions the reactivity. The catalyst structures
predicted from calculations are validated by the experiments. While
[
3]
and waste prevention.
During the last decades, three main strategies have emerged for
the direct amination of alcohols: (i) the borrowing hydrogen
2
) using either Ru or Ir complexes, and more
recently non-noble metal complexes based on Mn or Fe, (ii)
Tsuji-Trost type reactions for allylic alcohols using Pd or Ni
complexes, and (iii) Lewis-acid catalysis based on a variety of
[
4]
methodology (BH
[
5]
[6]
[
7]
[7a, 8]
[
2a, 2d]
a S
N
1-type mechanism is active in nitromethane, we propose a S
N
2
salts and ligands.
The latter is attractive as it uses non-
mechanism in toluene, thus rationalizing the much higher selectivity
when using this solvent. Also, unlike what is commonly assumed in
homogeneous catalysis, we show that different active species may
be active instead of only one.
noble metal, inexpensive, and low-toxic salts. Among the best
performing catalysts, triflates and triflimides stand out as Lewis
[9]
[10]
[11]
superacids. Metal triflates and triflimides, based on Ca, Al,
[
12]
[13]
[13c]
[13c]
[14]
[15]
[16]
[17]
[18]
In,
Yb,
La,
Hf,
Bi,
Cu,
Ag,
Hg,
and Au,
[
19]
including the parent triflic acid (HOTf), were found active for a
broad range of acid-catalyzed reactions. In particular, Mashima
and coworkers reported Al(OTf)
amination of secondary allylic or benzylic alcohols.
3
as a powerful catalyst for the
Introduction
[11b]
The
reaction proceeded to completion and with high selectivity in
nitromethane at mild temperature (25-50 °C) and short reaction
times (from 5 min to 6 h, typically 10-30 min). However, as a
major drawback, the reaction scope was limited to electron-poor
amine derivatives, such as amides, sulfonamides, carbamates,
Amines hold a substantial place among the intermediates used
and synthesized by the chemical industry, with a vast repertoire
[1]
of applications.
Among the different methods for amine
synthesis, the direct amination of alcohols constitutes an
attractive transformation, since alcohols (including biomass-
derived alcohols) are readily available, easy to handle and water
[11b]
and to activated alcohols (Scheme 1, left).
1
this work, R1 = H
previous
work, R
=
Ar
Me,
OH
[
a]
b]
P-A. Payard, Q. Gu, Dr. W. Guo, Q. Wang, Dr. M. Corbet, Dr. R.
Wischert, Dr. M. Pera-Titus
Eco-Efficient Products and Processes Laboratory (E2P2L), UMI
Al(OTf)3
MeNO2
2
Al(OTf)3
Ph
Ph
NHR2
H NR +
2
+ PhNH2
Ph
N
R1
H
Ph
toluene
3
2
464 CNRS – Solvay, 3966 Jin Du Road, Xin Zhuang Ind. Zone,
01108 Shanghai (China).
R2 = Boc, Cbz, CO Me, Ac,
2
Bz, 4-NO2-Ph, Ts,
...
E-mail:
raphael.wischert@solvay.com,
marc.pera-titus-
ext@solvay.com
[11b]
Scheme 1. Scope of the direct amination of alcohols catalyzed by Al(OTf)
3
.
[
P-A. Payard, Dr. L. Grimaud
PASTEUR, Département de chimie, École normale supérieure, PSL
Research University, Sorbonne Universités, UPMC Univ. Paris 06,
CNRS 75005 Paris (France).
With respect to the catalytic mechanism, there is general
consensus that substitution of OH-groups with C-, S-, and O-
nucleophiles proceeds via
presence of hard Lewis or Brønsted acids.
intermediates are generated by coordination of the alcohol to the
acidic center, and subsequent formation of an acid-OH species.
Racemization of optically active alcohols, and electronic and
solvent effects support such a mechanism. Due to their polar
N
nature, solvents typically used for S 1-type reactions, such as
N
a S 1-type mechanism, in the
[
c]
d]
Dr. C. Michel. Dr. W. Guo
Univ. Lyon, ENS de Lyon, CNRS UMR 5182, Université Claude
Bernard Lyon 1, Laboratoire de Chimie, F69342, Lyon (France).
[
2a, 2d]
Carbocation
-
[
Prof. P. Sautet
[2d]
Department of Chemical and Biomolecular Engineering and
department of Chemistry and Biochemistry, University of California,
Los Angeles, California, 90095 (USA).
[
10]
[14b, 19]
[11b, 13a, 16b]
Present addresses:
W. Guo
National Energy Center for Coal to Liquids, Synfuels China Co., Ltd,
Huairou District, Beijing 101400 (China).
dichloromethane,
dioxane,
nitromethane,
and
[
12, 14a]
water,
KPF for Bi(OTf)
the catalytic performance, most likely by generating more active
can stabilize ionic intermediates. Additives such as
[14b]
3
[10]
6
and Bu
4
NPF
6
for Ca(NTf
2
)
2
can enhance
−
-
−
Supporting information for this article is given via a link at the end of
the document.
2 6
species by exchange of TfO and NTf anions for PF .
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While a S
N
1-type mechanism appears to be predominant for a
(Table 1, entry 2), and an almost quantitative carbon balance
was achieved. Note, that in both solvents only trace amounts of
the secondary amine 4 and Friedel-Crafts products 5-6 were
formed. Less byproduct was again observed in toluene.
The markedly different reaction outcome for nitromethane and
toluene suggests different mechanisms. Therefore, to better
understand the different reactivity in both solvents and the need
of much higher temperature, compared to electron-poor amines
and activated secondary alcohols, a dedicated mechanistic
large majority of metal triflates, key aspects of the Lewis acid-
catalyzed amination reaction of alcohols remain unclear. This
lack of understanding can be certainly ascribed to the difficult
access to the catalyst structure under working conditions.
Indeed, detailed structural and spectroscopic data on metal
triflates is scarce, in particular in solution, with the notable
[
9, 20]
[21]
exception of recent ESI-MS
Duñach, Gal and coworkers. Likewise, few theoretical
and NMR studies reported by
[22]
investigations of metal triflate-catalyzed reactions of alcohols
3
study of the Al(OTf) -catalyzed amination reaction was
undertaken in both nitromethane and toluene.
[
22b, 23]
or ethers
exist. As a measure of Lewis acidity, the effective
charge density (i.e. the ratio between the DFT-calculated cation
charge and the effective ionic radius) was found to correlate with
Table 1. Conversion of benzyl alcohol, (BnOH, 1), yields, and carbon balance
(in %) for the reaction with aniline in two different solvents, according to
Scheme 2. Values obtained by GC analysis, using biphenyl as an internal
standard.
[
22b, 23]
the catalytic activity for the C-O bond cleavage of ethers.
Here, we extend the direct amination of alcohols catalyzed by
Al(OTf) to electron-rich amines and primary benzylic alcohols,
3
using the reaction between benzyl alcohol (BnOH) and aniline
as a model system (Scheme 1, right). We show that the
selectivity of the reaction strongly depends on the choice of the
solvent, with an unexpectedly favourable outcome in toluene, a
solvent typically not used for this class of reactions. We then
provide detailed insight into the structure of the catalyst under
working conditions, using different analytical methods. DFT
calculations are performed to rationalize the findings and the
reaction mechanism.
Conv.
1
Yield
4
Solvent
Carbon balance
3
5
6
a
a
Nitromethane
Toluene
63
41
26 (41)
37 (90)
1.2 2.9 2.2
0.3 1.1 0.8
59
96
a) Selectivity to N-phenylbenzylamine (3).
3
Nature of Al(OTf) in nitromethane and coordination of
benzyl alcohol
The nature of Al(OTf)
3
was first investigated in nitromethane by
different analytical methods (cyclic voltammetry, conductimetry,
H- and C-NMR spectroscopy). Cyclic voltammetry (CV) allows
Results and Discussion
1
13
the characterization of redox-active species by their oxidation
and reduction potentials. In this technique, the reactivity can be
assessed by considering that the reduction or oxidation currents
are proportional to the concentration of the electroactive
Amination reaction in nitromethane and toluene
First, we investigated the catalytic properties of Al(OTf)
3
in
nitromethane, a polar solvent typically used for metal triflate-
[25]
[11b]
species.
mM) exhibited two non-reversible reduction peaks (i.e. R
) centered at -0.55 V and -0.95 V vs. SCE, respectively
The CV of Al(OTf)
3
dissolved in nitromethane (10
catalyzed reactions.
For this purpose, a 1:2 mixture of benzyl
1
and
alcohol (BnOH) and aniline was heated in the presence of a
[
24]
R
2
catalytic amount of Al(OTf)
3
(Scheme 2).
Unlike the results
-1
(
Figure 1a). An increase of the scan rate up to 2 Vs modified
reported by Mashima and coworkers obtained with electron-poor
[
11b]
the relative intensity between both peak currents (Figure S1).
Such a behavior can be typically ascribed to the existence of an
equilibrium between two different species.
amine derivatives and secondary allylic or benzylic alcohols,
our reaction required very harsh conditions. Indeed, even at
60 °C under microwave irradiation, the primary amination
1
product N-phenylbenzylamine (3) was obtained with poor
selectivity (Table 1, entry 1). Besides, the carbon balance turned
out to be low, most likely due to the formation of oligomers.
a)
b)
1
0
0
Lower temperatures did not lead to any product.
Ph
Ph
Ph
Ph
N
-10
20
-30
Ph
N
H
c)
Ph
-
NH2
3
4
OH
Al(OTf)
µW, 160 °C, 2 h
solvent (C = 2
(5 mol %)
3
+
+
NH2
NH2
R1
M
)
-
-
40
50
2
R /R
1 3
1
2
(2 mmol)
(1 mmol)
R2
1
R2
-1.0
-0.5
5
6
Ph
-
0
1
-1
0
1
2
Scheme 2. Main products obtained in the amination reaction of benzyl alcohol
1, BnOH) with aniline (2).
E vs SCE / V
E vs SCE / V
(
Figure 1. CV towards reduction potentials recorded on a steady glassy carbon
disk electrode (d = 1 mm) in nitromethane containing n-Bu NBF (300 mM) at
(10 mM); b) Al(OTf) upon
addition of increasing amounts of BnOH (0 [in blue], 11 [in black] and 50 equiv
[in red]); and c) insert of b).
4
4
Unexpectedly, when the reaction was performed under the same
conditions, but in toluene, a non-polar solvent, the expected
product 3 was obtained with high selectivity (90%) and fair yield
-1
2
0 °C with a scan rate of 0.5 V s . a) Al(OTf)
3
3
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Chemistry - A European Journal
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[
28]
The addition of water increased the reduction peak current at R
1
1
2
tiny, this shift is consistent with the coordination of BnOH to
Al(III) and corresponds to a rapid equilibrium on the NMR
timescale.
at the expense of peak R
2
(Figure S2). The reduction peak R
[
26]
could thus be attributed to an Al-water complex, while peak R
is consistent with the reduction of nitromethane coordinated to
[
27]
Al(OTf)
observed in the presence of various Lewis acids such as LiNTf
LiBF and AlCl (Figure S3).
To assess any potential triflate dissociation,
conductivity measurements was performed in nitromethane at
different Al(OTf) concentrations. The conductivity of the parent
solution was found to be very low and a plot of the conductivity
vs. Al(OTf) concentration is characteristic of poorly dissociated
3
.
A similar reduction pattern for nitromethane was
Catalyst deactivation by aniline in nitromethane
2
,
3
Upon addition up to 1.5 equiv of aniline to a solution of Al(OTf) ,
no free aniline was present, as evidenced by the absence of its
characteristic oxidation peak at +1.0 V vs. SCE in the CV plot
4
3
a
series of
(
Figure 3a). CV towards negative potentials exhibited a new
reduction peak at -0.7 V vs. SCE (R ), together with a markedly
lower intensity of the reduction peak at -0.95 V (R ) (Figure 3b).
3
4
2
3
This observation is consistent with the formation of a complex
between Al(III) and aniline.
Upon addition of 3 equiv of aniline (Figure 3a), the reduction
peak at -1.0 V vs. SCE almost vanished. Moreover, the
electrolytes (Figure 2, ▲). This observation is consistent with
published reports establishing a weak dissociation of metal
[
20]
triflate salts in low-coordinating solvents such as nitromethane.
Additional CV experiments were conducted to investigate the
coordination of BnOH to Al(III). The reduction peak
decreased significantly upon BnOH addition (Figure 1b, c),
whereas the current intensity increased at a reduction potential
similar to R
a new peak (R
to Al(OTf) . This complex is expected to behave similarly to that
formed with water (reduced at R ), which could explain the
similar reduction potentials. These results underline the high
affinity of BnOH for Al(III), being able to displace nitromethane
under conditions similar to those of the catalytic reaction.
However, in analogy to water, coordination of BnOH does not
result in the dissociation of the triflate ions, as apparent from the
3
conductivity measured for Al(OTf) with an aniline excess (100
R
2
mM) exhibited higher values than for a solution of sodium triflate,
together with a linear-shaped curve that is consistent with the
formation of ionic species (Figure 2, ■). p-Fluoroaniline was
1
. This observation is likely due to the appearance of
19
used as F-NMR probe to study the complexation of aniline to
3
), which can be attributed to BnOH coordinated
1
9
3
Al(III). In the presence of 1 equiv of Al(OTf) , the F-NMR signal
3
shifted from -127 ppm to -110 ppm (fluorobenzene was used as
an internal standard at -112 ppm). This shift confirms the
coordination of aniline to Al(III), thus allowing the determination
of the stoichiometry of the complex using the Job plot method
1
(
Figure S5). The point-shaped plot obtained is indicative of a
large constant with a maximum observed at 0.6 corresponding
to a 3:2 complex. The latter result is consistent with the CV
curves, as free aniline was evidenced beyond 1.5 equiv of
plot of conductivity vs. Al(OTf)
excess BnOH (100 mM) (see Figure 2, Δ).
3
concentration in the presence of
aniline with respect to Al(OTf)
3
.
0
0
0
0
.6
.4
.2
.0
a)
b)
Al(OTf) - aniline
3
0
10
20
3
2
1
0
0
0
0
-
-
Na(OTf)
aniline
σ
-30
Al(OTf) - BnOH
3
-40
Al(OTf)3
R4
-50
R2
0
2
4
6
8
10
C / mmol.L-1
1.0
1.5
-1.0
-0.5
E vs SCE / V
E vs SCE / V
Figure 2. Conductivity of Al(OTf)
3
in nitromethane (▲), with excess BnOH
(
100 mM, Δ) and with excess aniline (100 mM, blue ■) as a function of the
Figure 3. CV recorded on a steady carbon disk electrode (d = 1 mm) in nitro-
o
Al(OTf)
3
concentration. For comparison, the conductivity of NaOTf in
methane containing n-Bu NBF (300 mM) at 20 C and at a scan rate of 0.5 V
4
4
-
.1
nitromethane (red ■) is also plotted.
s
. a) oxidation of Al(OTf)3 (10 mM) with 1.5 equiv of aniline [blue], 1.6 equiv
of aniline [black] and 1.8 equiv of aniline [red]; b) reduction of Al(OTf) (10 mM)
3
without aniline [blue], with 1 equiv of aniline [black] and 3 equiv of aniline [red].
To gain more insight into the nature of the possible reaction
intermediates, the complexes formed between BnOH and
1
13
Al(OTf)
0 equiv of Al(OTf)
two benzylic protons of BnOH was shifted to 4.64 ppm (Figure
3
were analyzed by H- and C-NMR. In the presence of
To further rationalize the potential competition between BnOH
and aniline, CV and NMR experiments were conducted in the
presence of excess BnOH. All these tests confirm that aniline
was able to displace BnOH from Al(III) (Figure S6, S7).
Moreover, when 1-phenylethanol was reacted with electron-poor
1
3
, the singlet at 4.63 ppm accounting for the
1
3
S4a). Comparable shifts were observed by C-NMR, with all
signals being shifted by about 0.5 ppm (Figure S4b, c). Even if
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Chemistry - A European Journal
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p-tolylsulfonamide (2 equiv) at room temperature in the
presence of 10%mol Al(OTf) and aniline (2 equiv), no amination
3
soluble in toluene, as evidenced by the integration of the signal
at -78 ppm for ligated triflates. This behavior does not exclude,
however, a competition between BnOH and p-fluoroaniline
under catalytic conditions. Indeed, when both BnOH and p-
product was observed. Conversely, when the same reaction was
performed under the very same conditions as in ref. [11b], but in
the absence of aniline, the amination product was obtained (see
Figure S8 and corresponding discussion in the supporting
information). Overall, we can conclude that, in nitromethane,
3
fluoroaniline were in excess with respect to Al(OTf) , the p-
19
fluoroaniline signal in F NMR shifted from -127 ppm to -121
ppm, proving that a significant quantity of p-fluoroaniline was
ligated to Al(III).
3
Al(OTf) is deactivated by the formation of cationic complexes
featuring aniline as ligand (Scheme 3a). Hence, BnOH is not
expected to coordinate to Al(III), which is consistent with the
Overall, the above results point out that the nature of Al(OTf)
under catalytic conditions depends to an important extent on the
3
poor selectivity observed under reaction conditions (see Table 1). polarity of the solvent. While polar solvents such as
nitromethane favor its dissociation and accordingly the coor-
Competition between BnOH and aniline for Al in toluene
dination with electron-rich ligands such as aniline, no charged
species are formed in the presence of non-polar solvents such
as toluene (Scheme 3b). In this view, it is reasonable to expect a
different catalytic mechanism as a function of the solvent. In
Next, we studied the coordination of BnOH and aniline to
Al(OTf)
toluene. However, upon addition of 2 equiv of aniline, a single
reduction plateau at E1/2 = -0.5 V vs. SCE (R ) was observed by
CV, using a stationary method on an ultramicroelectrode.
Likewise, Al(OTf) with 10 equiv of BnOH exhibited a single
reduction plateau at E1/2 = -1.0 V vs. SCE (R ) (Figure 4). When
0 equiv of aniline were added to a solution of Al(OTf) (10 mM)
3 3
in toluene. Al(OTf) alone proved to be insoluble in
N
particular, a S 1-type mechanism seems very unlikely in toluene.
5
[
29]
BnOH
aniline
a)
Al(OTf)
3
(BnOH)
n
Al(OTf)
3
(H
2
O)x(MeNO
2
)y
3
Al(OTf) (aniline)
z
3
6
2
3
Al(OTf)
2
(BnOH)
+
n
Al(OTf)
2
(H
2
O)x(MeNO
2
)y
Al (OTf) (aniline)
2
5
3
and 10 equiv of BnOH, two reduction plateaus associated with
BnOH- and aniline-ligated Al(III), respectively, were observed.
Still, the equilibrium was in favor of the BnOH complex and up to
+
+
OTf
OTf
OTf
80 equiv of aniline were necessary to fully shift the equilibrium
towards coordinated aniline (Figure 4). Note, that this situation
contrasts with the BnOH and aniline coordination pattern in nitro-
methane (vide supra).
Al (OTf) (aniline)
+
OTf
b)
Al(OTf)
3
(BnOH)
x
Al(OTf)
3
2
5
3
toluene
non-polar)
nitromethane
(polar)
(
0
3
Scheme 3. a) Deactivation of Al(OTf) in the presence of aniline in nitro-
methane by the formation of ionic complexes, b) simplified coordination
-
-
-
-
-
-
-
-
1
2
3
4
5
6
7
8
3
pattern of Al(OTf) complexes in toluene and nitromethane under catalytic
R6
conditions.
R5
Determination of the structure of the catalyst by DFT
calculations
To validate the experimental findings, interpret them in detail
and provide mechanistic insight, we performed a DFT study,
focusing on the surprisingly selective amination reaction in
toluene. Calculations were performed at the B3LYP-D3(BJ) /
def2-TZVP (COSMO) // BP86-D3(BJ) / def2-SV(P) level (see the
supporting information for details, and validation of the method
against CCSD(T) reference calculations, Tables S1 and S2).
-
2.0
-1.5
-1.0
-0.5
0.0
0.5
E vs SCE / V
Figure 4. CV recorded on a steady gold ultramicroelectrode (d = 25 µm) in
o
-1
3
Al(OTf) can coordinate up to three additional ligands, assuming
toluene containing n-hex
From top to bottom: complexation of Al(OTf)
blue), 10 equiv of BnOH and 30 equiv of aniline (green), and 10 equiv of
BnOH and 80 equiv of aniline (red).
4
NBF
4
(60 mM) at 20 C with a scan rate of 0.01 V s .
monodentate coordination of the triflate anions (as opposed to
3
(10 mM) with 10 equiv of BnOH
2
(
the bidentate κ -coordination in free Al(OTf)3, Figure 5a). The
binding free energy (ΔGbind) of n ligands L to Al(OTf)
as the free energy associated with the formation of a [Al(OTf)
complex from Al(OTf) and n ligands L. At 25 °C in toluene this
binding for a single ligand is strongest for BnOH (ΔGbind = -87 kJ
3
is defined
3 n
L ]
The competition between BnOH and aniline was further
confirmed by F-NMR spectroscopy, using p-fluoroaniline. In the
presence of 5 equiv of p-fluoroaniline, Al(OTf) was not soluble
in toluene and this situation persisted even up to 40 equiv of p-
fluoroaniline. From the integration of the p-fluoroaniline signal, it
appeared that 1 equiv of p-fluoroaniline was coordinated to a
non-soluble Al(III)-complex. In contrast, in the presence of
3
1
9
-
1
-1
mol ), followed by aniline (ΔGbind = -75 kJ mol ) and the
3
-1
reaction products, N-phenylbenzylamine (Gbind = -72 kJ mol )
and water (ΔGbind
-1
= -70 kJ mol ) (Figure 5b-e and Table S3,
entries 1-4). These values agree well with the experimentally
observed stronger binding of BnOH compared to aniline (vide
supra). Note, that alcoholysis of Al(OTf)
3
by BnOH, leading to
excess BnOH (30 equiv), Al(OTf)
3
(2 mM) was completely
the formation of Al(OTf) (BnO) and HOTf, was found to be much
2
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Chemistry - A European Journal
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less favorable than binding of BnOH to Al(III) (ΔG = +32 vs.
These O atoms can now participate in stabilizing H-bonds with
protons from the molecules coordinated to Al(III) (Figure 5b-d).
The strongest H-bonds are formed with O-bound molecules, i.e.
BnOH (1 bond with d(OOTf-H) = 1.50 Å) and water (2 bonds with
d(OOTf-H) = 1.59-1.60 Å), while much weaker bonds are formed
-1
ΔGbind = -87 kJ mol , vide supra). The high affinity of BnOH for
Al(III) can be rationalized a priori by the high oxophilicity of
[30]
Al(III), but it is possible to analyze more in detail the nature of
the interaction by NBO charge analysis (Table 2): Both Al-O and
Al-N bonds result mainly from ionic interactions, as apparent
from charge separation (polarization) upon coordination. In the
case of BnOH, the formal positive charge on Al(III) increases
from +1.92 to +2.17, while the formal negative charge of the O of
BnOH increases from -0.71 to -0.87, thus clearly demonstrating
electron transfer from Al to O. For aniline coordination, while
polarization of the N atom of aniline is comparable to that of the
O atom of BnOH (-0.19 vs. -0.16, respectively), the effect on
Al(III) is much smaller (+0.14 vs. +0.25 for BnOH). Also, the Al-O
bond is much shorter than the Al-N bond, leading to a stronger
coulombic interaction for the O atom. All these observations are
consistent with a hard Lewis acid / hard Lewis base interaction,
favoring O-coordination.
with the N-containing aniline and N-phenyl benzylamine (d(OOTf
-
H) = 1.84-2.03 Å).
The energetic gain of binding a second BnOH molecule to
-1
3
Al(OTf) (BnOH) is smaller (-58 kJ mol , see Table S3, entry 5)
than for the first molecule, probably because the Lewis acidity of
Al(III) is reduced by the already bound BnOH. Note that for the
other molecules, the relative binding strengths (i.e BnOH >
aniline > H
2
O) are preserved (Table S3, entries 6-7). The
rd
binding of a 3 BnOH molecule on Al(III) results in a strong
stabilization by -70 kJ mol vs. Al(OTf)
-1
3 2
(BnOH) , probably
because a very stable octahedral structure is formed (ΔGbind = -
−1
215 kJ mol , Figure 6a and Table S3, entry 8). Note that when
only one type of molecule is coordinated, both fac and mer
isomers can be formed with either all triflate ions and ligands
grouped on opposite sides of the octahedron (fac), or occupying
the octahedral planes (mer). The latter was found more stable
-1
than fac-coordination by 32, 51 and 14 kJ mol for BnOH,
aniline and water, respectively, most likely because steric and
electrostatic repulsion between the coordinated molecules and
the triflate anions is minimized (Table S3). The higher binding
strength of BnOH, compared to aniline and water, is conserved
-1
for the binding of 3 molecules (ΔGbind = -215 vs. -183 kJ mol
and -154 kJ mol , respectively, see Figure 6a-c).
-1
Figure 5. Optimized structures of a) free Al(OTf)3, b-c) after coordination of
reactants, d-e) after coordination of products, and calculated binding free
-
1
energies (ΔGbind at 25 °C in toluene, kJ mol , indicated in brackets).
[
31]
Table 2. Selected NBO partial charges estimated by NBO,
O(H)CH and Al-N(H) bond lengths for Al(OTf) , Al(OTf)
and Al(OTf) (aniline). Changes, compared to free Al(OTf) , BnOH and aniline,
are indicated in brackets.
and Al-
2
C
5
H
5
2
C
5
H
5
3
3
(BnOH)
3
3
3 3 3
Al(OTf) Al(OTf) (BnOH) Al(OTf) (aniline) BnOH aniline
charge on Al
charge O/N
d(Al-O/N) (Å)
1.92
2.17 (+0.25)
-0.87 (-0.16)
1.83
2.06 (+0.14)
-0.96 (-0.19)
1.97
-0.71 -0.79
3
Figure 6. Selected optimized structures of complexes of Al(OTf) with 3
molecules of BnOH, aniline, or water; and calculated binding free energies
-
1
1 2
q q /d
-1.0316
-1.0039
(ΔGbind at 25 °C in toluene, kJ mol , indicated in brackets).
A second interaction likely contributes to the difference between
BnOH and aniline. The coordination of the reactant and product
molecules leads to decoordination of one or several O atoms of
We also calculated all possible mixed combinations with n BnOH
l l aniline and m water molecules (n + l + m = max. 3, see Table
3 3
S3). This analysis confirms that mer-Al(OTf) (BnOH) is indeed
2
the initially κ -coordinated triflate anions from the Al(III) center.
the most stable structure in toluene, thus corroborating and
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Chemistry - A European Journal
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FULL PAPER
quantifying the experimental findings, which clearly indicated
preferential binding of BnOH in toluene. BnOH is present in all
most stable mixed configurations (see for example Figure 6d
and Table S3, entries 8-12) and all combinations without BnOH
are significantly less stable. The charge transfer (withdrawal of
electrons) from the ligands to Al decreases with the number of
ligands, going from +0.25 for 1 BnOH (see Table 2) to 0.24, and
transfer and decoordination of N-phenylbenzylamine leads to
-1
Al(OTf)
Al(OTf)
3
(BnOH)
(BnOH)
2
(H
. Unlike the most stable isomer found for
2
O) (∆G = -1 kJ mol ), and release of water to
3
2
coordination of 2 BnOH (Table S3, entry 5), the resulting
structure is five-coordinate and therefore less stable (∆G = +70
-1
kJ mol ). Finally, BnOH coordination leads back to
-1
Al(OTf)
3 3
(BnOH) (∆G = -18 kJ mol ), the resting state of the
0
.15 for 2 and 3 BnOH, respectively (see Table S4). At the same
time, the average bond length Al-O(H)CH increases from
.83 to 1.93 Å (see Table S4). Both factors are consistent with a
decreasing binding energy per ligand (Figure S9a).
The binding free energies were in addition computed at 160 C
reaction temperature) (Table S3, Figure S9b). As expected, at
this temperature, binding to Al(OTf) is much less favorable.
Low-coordinated and potentially more reactive metastable
complexes such as Al(OTf) (BnOH) and Al(OTf) (BnOH) are
catalyst.
2
5 5
C H
1
°
(
3
3
2
3
o
thus accessible under reaction conditions, but unlikely at 25 C,
at which CV and conductometry tests were performed. In what
follows, Al(OTf)
3
(BnOH)
3
is the most stable structure in toluene,
Figure 8. Transition state (TS S
N
2) and ion-pair for the reaction of aniline with
Al(OTf)
3
(BnOH) in toluene; selected distances are indicated in Å.
3
i.e. the resting state of the catalyst, while less stable structures
will be called reactive states.
Reaction mechanism
117
NH2
TS SN
2
In polar solvents, a S
the direct amination reaction of BnOH. Indeed, dissociation of
N
1-type mechanism can be proposed for
H
H
O H
–
70
Al(OTf)
3
(BnOH)
3
into [Al(OTf)
3
(BnOH)
2
(OH)] and
a
benzyl
Al(OTf)
3
)(BnOH)
2
Al(OTf)
3
(BnOH)
2
cation is feasible in nitromethane, albeit associated with a
O
NH2
H
H
‡
-1
OH
sizeable barrier (∆G = +97 kJ mol ). Combined with the
energetic cost to displace the strongly bound aniline from the
Al(III) center (vide supra), this explains why much harsher
conditions are necessary than for the more reactive secondary
alcohols, and less basic and thus less coordinating amine
2
1
0
–1
3
Al(OTf) (BnOH)
2
(BnOH)
–18
H
N
H
N
H
3
Al(OTf) (BnOH)
2
(BnOH)
–21
[
11b]
derivatives used by Mashima.
species is very likely responsible for side reactions and in turn
for the low selectivity. In contrast, in toluene, where a S
The formation of cationic
3
+
O
H
Al(OTf)
3
(BnOH)
2
Al(OTf)
3
(BnOH)
2
(H
2
O)
N
1
ion-pair
-1
mechanism is impossible (∆G = +272 kJ mol ), one can more
reasonably assume a S 2-type mechanism, in which aniline
Figure 9. Calculated free energy profile for the direct amination of benzyl
alcohol with aniline to N-phenylbenzylamine and water in toluene solvent. Free
N
-
1
attacks the C-atom of BnOH coordinated to Al(III), thus avoiding
the formation of ionic species.
energies (∆G at 160 °C, kJ mol ) are defined relative to separate
Al(OTf) (BnOH) and aniline.
3
3
3 3
Starting from Al(OTf) (BnOH) , three different C-O bonds can be
broken. Since the structures of the transition states are similar,
we only report the most favorable case (Figure 8a and Figure 9,
Effect of coordinated species on the catalyst efficiency
In addition to Al(OTf) (BnOH) , the resting state of the catalyst
‡
-1
3
3
∆
G
= 117 kJ mol ; attack on the other two benzylic carbon
-1
(i.e. the most stable situation), we studied reactive states of the
catalyst, i.e. less stable structures in which one or several BnOH
have been exchanged by either aniline or water. The height of
atoms is slightly less favorable by 3 and 13 kJ mol ). The
transition state features trigonal-bipyramidal coordination and
2
sp -hybridization of carbon, as expected for a S
N
2 reaction. The
‡
the intrinsic barrier (ΔG intr) provides a measure of the reactivity
O-C-N angle formed between the breaking C-O and the forming
C-N bond is close to linear (162°). Note, that a triflate ligand
stabilizes the transition state by forming a H-bond with one of
the protons of aniline. The product of an intrinsic reaction
coordinate (IRC) run starting from the transition state converges
‡
of each reactive state, while the total barrier (ΔG tot) compares
the reactivity with that of Al(OTf)
Al(OTf) (BnOH) (X) and Al(OTf) (BnOH)(X)
aniline, the structures of the transition state and ion-pairs (Figure
S10a-d) are very similar to those found for Al(OTf) (BnOH) . As
a result, the intrinsic barriers are similar (Table 3, entries 2-5)
3
(BnOH)
3
(Table 3). For both
3
2
3
2
with X = H O or
2
3
3
to a stable structure in which protonated N-phenyl benzylamine
−
is bound to [Al(OTf)
=
3
(BnOH)
2
(OH)] (Figure 8b and Figure 9, ∆G
‡
-1
-1
(∆G intr = 117 kJ mol , Table 3, entry 1), while in the case of
-21 kJ mol ). This structure can be interpreted either as an
‡
3 2 2
Al(OTf) (BnOH) (H O) the barrier is even lower (∆G intr = +108
kJ mol , Table 3, entry 3). This means that for coordination of 3
ion-pair, or as an acid-base adduct in which the basic N of the
amine product interacts with the proton of the water molecule,
which, in turn, is acidified by its coordination to Al(III). Proton
-1
ligands to Al(III), the nature of the ligands has no significant
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Chemistry - A European Journal
10.1002/chem.201801492
FULL PAPER
[
11b]
effect on the reactivity of coordinated BnOH. However, given the
lower stability of the reactive states compared to
derivatives
to activated primary alcohols and electron-rich
amines, by studying the model reaction of benzyl alcohol (BnOH)
an aniline. By combining experiments with DFT simulations, we
were able to provide detailed insight into the structure of the
catalyst and the mechanism of the reaction, which were found to
strongly depend on the type of solvent (polar vs. non-polar).
Competition between aniline and benzyl alcohol was evidenced
both by NMR spectroscopy and cyclic voltammetry, and proved
to be critical to explain how the solvent conditions the reactivity.
The strong affinity of aniline for Al(III) in nitromethane solvent,
which can be attributed to the formation of ionic species, is
responsible for catalyst deactivation and very low selectivity.
Al(OTf)
3 3
(BnOH) , the cost for ligand exchange has to be
accounted for. Indeed, when only 1 BnOH is exchanged for
‡
-1
aniline or water, the effect is small, (∆G tot = 121-123 kJ mol ,
Table 3, entries 2-3), but when 2 ligands are exchanged, the
‡
reaction becomes significantly more difficult (∆G tot = 140-151 kJ
-1
mol , Table 3, entries 4-5).
Table 3. Calculated intrinsic free energy barrier with respect to the reactive
‡
‡
state (∆G intr) and aniline, total free energy barrier (∆G tot) with respect to the
resting state Al(OTf) (BnOH) and aniline, and partial charge on the Al atom
calculated by NBO (difference vs. Al(OTf)
3
3
3
(BnOH)
3
in brackets); free energies
-
1
N
Under such conditions, a S 1-type mechanism is active. In
in toluene at 160 °C (kJ mol )
contrast, in toluene, the reaction is very selective, leading to
almost exclusive formation of the desired N-phenylbenzylamine.
In this case, competition of BnOH and aniline for Al(III) binding is
in favor of BnOH, as shown experimentally and validated by
‡
‡
Entry
Reactive state
∆G intr
117
117
108
119
119
71
∆G tot
117
121
123
140
151
155
Charge on Al
2.09
1
2
3
4
5
6
Al(OTf)
Al(OTf)
Al(OTf)
Al(OTf)
Al(OTf)
Al(OTf)
3
3
3
3
3
3
(BnOH)
(BnOH)
(BnOH)
3
2
2
(Aniline)
(H O)
2.06 (-0.03)
2.03 (-0.06)
2.05 (-0.04)
2.01 (-0.08)
2.17 (+0.08)
2
DFT calculations, predicting the formation of Al(OTf)
the most stable complex (resting state of the catalyst). The
calculations strongly support a S 2 mechanism in which aniline
3 3
(BnOH) as
(BnOH)(Aniline)
2
(BnOH)(H
(BnOH)
2 2
O)
N
attacks the C-atom of BnOH coordinated to Al(III), thus avoiding
the formation of ionic species, and leading to much higher
selectivity. To our knowledge, it is the first time that such type of
mechanism is proposed for metal triflate-catalyzed substitution
reactions. Also, instead of a single active species, as commonly
assumed in homogeneous catalysis, we find that several
species, generated by exchange of coordinated BnOH with
water or aniline, can be active. Further investigations about how
the solvent, reactants and products condition the reactivity of
metal triflates are currently underway in our laboratories.
Finally, we also studied the reactivity of the low-coordinated
complex Al(OTf) (BnOH). Not surprisingly, the energy barrier for
the S 2 reaction is very low (∆G intr = 71 kJ mol , Figure S10e),
most likely because of its higher Lewis acidity, as apparent from
the higher partial charge on Al(III) compared to coordination by 3
ligands (Table 3, last column). However, as already mentioned,
3
‡
-1
N
3 3 3 2
starting from Al(OTf) (BnOH) , the formation of Al(OTf) (BnOH)
and Al(OTf) (BnOH) by successive losses of BnOH is
3
-1
associated with an energetic cost of 55 and 29 kJ mol ,
respectively (Table S3, entries 1, 5, and 8). Overall, the
energetic cost to generate Al(OTf)
reactivity, leading to an overall barrier of ∆G tot = 155 kJ mol
Table 3, entry 6), which is significantly higher than that for the
3
(BnOH) outweighs its higher
‡
-1
Acknowledgements
(
fully coordinated resting state of the catalyst, or other reactive
states. It is therefore unlikely that the low-coordinated complex
Al(OTf) (BnOH) contributes to the observed reactivity.
3
Another way of demonstrating that several species (resting state
and reactive states) simultaneously participate in the catalytic
event, is to calculate their contribution to the overall reaction rate.
The authors would like to express their gratitude to Solvay,
CNRS, PSL, ENS Paris, ENS de Lyon,UPMC and UCLA for
funding. P.A. Payard is grateful to ENS Paris Saclay for a PhD
grant. J. Lai (E2P2L) is acknowledged for useful discussions.
Keywords: Amination
•
Alcohol
•
Aluminum Triflate
•
The relative concentrations of the resting state Al(OTf)
and the reactive states Al(OTf) (BnOH) (Aniline) and
Al(OTf) (BnOH) (H O), are 74 %, 24 %, and 1.1 % (calculated
3 3
(BnOH) ,
Nucleophilic Substitution • DFT• Homogeneous Catalysis
3
2
3
2
2
[1]
(a) H. A. Wittcoff, B. G. Reuben, J. S. Plotkin, Industrial Organic
Chemicals, 2nd ed., Wiley, NY, 2004; (b) S. A. Lawrence, Amines:
Synthesis Properties and Applications, Cambridge University:
Cambridge, 2004; (c) B. R. Brown, The Organic Chemistry of Aliphatic
Nitrogen Compounds, Cambridge University: Cambridge, 2004.
from a Boltzmann distribution, see Table S3). The former two
species clearly predominate. However, while the concentration
of Al(OTf)
contribution of 12 % to the overall (compound) reaction rate
Table S5) due to its higher reactivity (vide supra). In a different
3 2 2
(BnOH) (H O) is low, this species has a sizeable
(
[2]
(a) E. Emer, R. Sinisi, M. G. Capdevila, D. Petruzziello, F. De Vincentiis,
P. G. Cozzi, Eur. J. Org. Chem. 2011, 2011, 647-666; (b) M. Pera-Titus,
F. Shi, ChemSusChem 2014, 7, 720-722; (c) S. Bähn, S. Imm, L.
Neubert, M. Zhang, H. Neumann, M. Beller, ChemCatChem 2011, 3,
context (heterogeneous catalysis), some of us have recently
highlighted the importance of such highly reactive metastable
[32]
species.
1853-1864; (d) A. Baeza, C. Nájera, Synthesis 2014, 46, 25-34.
[
3]
4]
B. Trost, Science 1991, 254, 1471-1477.
[
(a) T. D. Nixon, M. K. Whittlesey, J. M. J. Williams, Dalton Trans. 2009,
753-762; (b) G. Guillena, D. J. Ramón, M. Yus, Chem. Rev. 2010, 110,
Conclusion
1611-1641; (c) J. L. Klinkenberg, J. F. Hartwig, Angew. Chem. Int. Ed.
2011, 50, 86-95; (d) C. Gunanathan, D. Milstein, Science 2013, 341,
3
We have extended the Al(OTf) -catalyzed direct amination of
activated secondary alcohols with electron-poor amine
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201801492
FULL PAPER
1
229712; (e) Q. Yang, Q. Wang, Z. Yu, Chem. Soc. Rev. 2015, 44,
[26] The presence of adventitious water in the experiment can be due either
to the commercially available nitromethane (98.5% purity, kept on
molecular sieves (3 Å)) or to the hygroscopy of aluminum triflate (kept
2305-2329.
[5]
[6]
[7]
J. Neumann, S. Elangovan, A. Spannenberg, K. Junge, M. Beller,
Chem. Eur. J. 2017, 23, 5410-5413.
2 5
under vacuum on anhydrous P O ).
B. Emayavaramban, M. Roy, B. Sundararaju, Chem. Eur. J. 2016, 22,
[27] F. Prieto, I. Navarro, M. Rueda, J. Phys. Chem. 1996, 100, 16346–
3952-3955.
16355.
(a) H. Bricout, J.-F. Carpentier, A. Mortreux, J. Mol. Cat. A: Chem 1998,
3
[28] Comparable shifts due to the formation of alcohol-Al(OTf) complexes
1
36, 243-251; (b) Y. Gumrukcu, B. de Bruin, J. N. H. Reek, Catalysts
were observed by Dunach and collaborators in the mechanistic study of
the hydroalkoxylation of unactivated olefins, see ref [22a]
[29] In low polar solvents, the use of ultramicroelectrodes is mandatory due
to ohmic drop issues, see : C. Amatore, F. Pluger, Organometallics
1990, 9, 2276-2282.
2015, 5, 349-365; (c) S. Sawadjoon, P. J. R. Sjoberg, A. Orthaber, O.
Matsson, J. S. M. Samec, Chem. Eur. J. 2014, 20, 1520-1524; (d) J.
Muzart, Eur. J. Org. Chem. 2007, 2007, 3077-3089.
[8]
(a) H. Bricout, J.-F. Carpentier, A. Mortreux, Tetrahedron 1998, 54,
1
073-1084; (b) Y. Kita, H. Sakaguchi, Y. Hoshimoto, D. Nakauchi, Y.
Nakahara, J.-F. Carpentier, S. Ogoshi, K. Mashima, Chem. Eur. J.
015, 21, 14571-14578.
[30] K. P. Kepp, Inorg. Chem. 2016, 55, 9461-9470.
[31] (a) J. P. Foster, F. Weinhold, J. Am. Chem. Soc. 1980, 102, 7211-7218;
(b) A. E. Reed, L. A. Curtiss, F. Weinhold, Chem. Rev. 1988, 88, 899-
926.
2
[
[
[
9]
J.-F. Gal, C. Iacobucci, I. Monfardini, L. Massi, E. Duñach, S. Olivero, J.
Phys. Org. Chem. 2013, 26, 87-97.
[32] G. Sun, P. Sautet, J. Am. Chem. Soc., 2018, 140, 2812–2820.
10] S. Haubenreisser, M. Niggemann, Adv. Synth. Catal. 2011, 353, 469-
74.
11] (a) M. Gohain, C. Marais, B. C. B. Bezuidenhoudt, Tetrahedron Lett.
012, 53, 1048-1050; (b) T. Ohshima, J. Ipposhi, Y. Nakahara, R.
4
2
Shibuya, K. Mashima, Adv. Synth. Catal. 2012, 354, 2447-2452.
12] J.-M. Yang, R. Jiang, L. Wu, X.-P. Xu, S.-Y. Wang, S.-J. Ji,
Tetrahedron 2013, 69, 7988-7994.
[
[
13] (a) W. Huang, Q.-S. Shen, J.-L. Wang, X.-G. Zhou, Chin. J. Chem.
2008, 26, 729-735; (b) W. Rao, X. Zhang, E. M. L. Sze, P. W. H. Chan,
J. Org. Chem. 2009, 74, 1740-1743; (c) M. Noji, T. Ohno, K. Fuji, N.
Futaba, H. Tajima, K. Ishii, J. Org. Chem. 2003, 68, 9340-9347.
[14] (a) R. Jiang, C.-X. Yuan, X.-P. Xu, S.-J. Ji, Appl. Organomet. Chem.
2012, 26, 62-66; (b) H. Qin, N. Yamagiwa, S. Matsunaga, M. Shibasaki,
Angew. Chem. Int. Ed. 2007, 46, 409-413.
[15] W. Rao, P. Kothandaraman, C. B. Koh, P. W. H. Chan, Adv. Synth.
Catal. 2010, 352, 2521-2530.
[16] (a) X. Giner, P. Trillo, C. Nájera, J. Organomet. Chem. 2011, 696, 357-
361; (b) B. Sreedhar, P. Surendra Reddy, M. Amarnath Reddy, B.
Neelima, R. Arundhathi, Tetrahedron Lett. 2007, 48, 8174-8177.
17] H. Yamamoto, E. Ho, I. Sasaki, M. Mitsutake, Y. Takagi, H. Imagawa,
M. Nishizawa, Eur. J. Org. Chem. 2011, 2011, 2417-2420.
[
[
18] (a) V. Terrasson, S. Marque, M. Georgy, J.-M. Campagne, D. Prim, Adv.
Synth. Catal. 2006, 348, 2063-2067; (b) H. Hikawa, H. Suzuki, Y.
Yokoyama, I. Azumaya, J. Org. Chem. 2013, 78, 6714-6720; (c) T.
Ohshima, Y. Nakahara, J. Ipposhi, Y. Miyamoto, K. Mashima, Chem.
Commun. 2011, 47, 8322-8324; (d) B. Biannic, A. Aponick, Eur. J. Org.
Chem. 2011, 2011, 6605-6617; (e) M. Georgy, V. Boucard, O. Debleds,
C. D. Zotto, J.-M. Campagne, Tetrahedron 2009, 65, 1758-1766.
[19] P. Trillo, A. Baeza, C. Nájera, Eur. J. Org. Chem. 2012, 2012, 2929-
2934.
[
20] (a) J.-F. Gal, C. Iacobucci, I. Monfardini, L. Massi, E. Duñach, S.
Olivero, J. Am. Soc. Mass. Spectrom. 2012, 23, 2059-2062; (b) G.
Compain, L. Sikk, L. Massi, J. F. Gal, E. Dunach, ChemPhysChem
2
017, 18, 683-691; (c) C. Iacobucci, N. Jouini, L. Massi, S. Olivero, F.
De Angelis, E. Duñach, J.-F. Gal, ChemPlusChem 2017, 82, 498-506;
d) I. Monfardini, L. Massi, E. Dunach, S. Olivero, J.-F. Gal, Chem.
(
Commun. 2010, 46, 8472-8474.
[21] Y. Koito, K. Nakajima, H. Kobayashi, R. Hasegawa, M. Kitano, M. Hara,
Chem. Eur. J. 2014, 20, 8068-8075.
[
22] (a) L. Coulombel, M. Rajzmann, J.-M. Pons, S. Olivero, E. Duñach,
Chem. Eur. J. 2006, 12, 6356-6365; (b) Z. Li, R. S. Assary, A. C. Atesin,
L. A. Curtiss, T. J. Marks, J. Am. Chem. Soc. 2013, 136, 104-107.
23] R. S. Assary, A. C. Atesin, Z. Li, L. A. Curtiss, T. J. Marks, ACS Catal.
[
[
[
2013, 3, 1908-1914.
24] The use of more than one equivalent of aniline was required to avoid
the formation of large amounts of dibenzylamine as by-product.
25] A. Jutand, Chem. Rev. 2008, 108, 2300-2347.
This article is protected by copyright. All rights reserved.

Chemistry - A European Journal
10.1002/chem.201801492
FULL PAPER
FULL PAPER
Pierre-Adrien Payard, Qingyi Gu,
Wenping Guo, Qianran Wang, Matthieu
Corbet, Carine Michel, Philippe Sautet,
Laurence Grimaud, Raphael Wischert,*
and Marc Pera-Titus*
Al(OTf)
3
PhNH2
Ph
Al(OTf)
3
(BnOH)
3
Ph
N
S 2
H
N
[
Al(OTf)(PhNH
OTf
2
)]
amination
nitromethane
product
Al(OTf)
3
(BnOH)
toluene
unreactive species
Page No. – Page No.
Direct
Amination
of
Alcohols
Catalyzed by Aluminum Triflate: an
The use of aluminum triflate, Al(OTf)
3
as catalyst for the direct amination of
Experimental
Study
and
Computational
activated primary alcohols with electron-rich amines is reported. Competition
between aniline and benzyl alcohol is evidenced both by NMR spectroscopy and
cyclic voltammetry, and is shown to be critical to explain how the solvent conditions
the reactivity in polar and non-polar solvents, with a high selectivity in toluene.
Density functional theory (DFT) calculations rationalize the impact of the catalyst
N
structure on the reactivity, and support an unprecedented S 2-type mechanism in
toluene.
This article is protected by copyright. All rights reserved.