New NHC- silver and gold complexes active in A3-coupling (aldehyde-alkyne-amine) reaction

Article abstract of DOI:10.1016/j.mcat.2019.110570

Silver and gold complexes bearing unsaturated N-heterocyclic carbene ligands, with unsymmetrical N-substituents and hydrogen or chlorine on backbone, have been synthetized and their efficiency tested in A³-coupling (aldehyde–alkyne–amine) react

Full text of DOI:10.1016/j.mcat.2019.110570

Molecular Catalysis 480 (2020) 110570
Contents lists available at ScienceDirect
Molecular Catalysis
journal homepage: www.elsevier.com/locate/mcat
3
New NHC- silver and gold complexes active in A -coupling (aldehyde-
alkyne-amine) reaction
⁎
Annaluisa Mariconda , Marco Sirignano, Chiara Costabile, Pasquale Longo
Department of Chemistry and Biology (DCB), University of Salerno, via Giovanni Paolo II, 132I-84084, Fisciano, SA, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords:
Silver and gold complexes bearing unsaturated N-heterocyclic carbene ligands, with unsymmetrical N-sub-
3
Silver complexes
Gold complexes
NHC ligand
stituents and hydrogen or chlorine on backbone, have been synthetized and their efficiency tested in A -coupling
(
aldehyde–alkyne–amine) reactions. Gold complexes showed higher activity than corresponding silver ones,
even if the significant role of the backbone substituents should not be neglected. Indeed, complexes with chlorine
substituted backbone were more efficient than hydrogen analogous. According to DFT calculations, electronic
differences among complexes are able rationalize the different catalytic behavior, whereas steric properties play
a minor part.
3
A -coupling reaction
1
. Introduction
however, those which have proved to be the most interesting, are based
on coin metals: copper, silver and gold [18–21]. These metals can co-
The most efficient method for preparing propargylamines is the
ordinate terminal alkynes by forming π complexes, thereby increasing
the acidity of the CeH bond. Because of this increased acidity, weak
basic amines can deprotonate the CH bond and generate the desired
organometallic alkynyl nucleophile [22]. The reaction of this acetylide
with iminio, which is obtained in situ by reaction of the aldehyde with
the amine, produces the desired product and regenerates the catalyst
(see Scheme 2) [22].
3
multicomponent reaction (MCR) commonly referred to as A -coupling
(
aldehyde–alkyne–amine) reaction [1,2] (see Scheme 1). The MCR is
very interesting from an environmental point of view, as it allows the
synthesis of complex molecules, reducing the total time necessary to
obtain the desired product, by minimizing solvents and energy and
decreasing the production of by-products [3], since water is the only by-
product with the desired compound.
Starting from the statement that many silver and gold complexes
stabilized by N-heterocyclic carbene ligands are able to give this reac-
tion [23] and considering our interest in these compounds [24–26], we
have explored the catalytic behavior of silver and gold NHC-metal
complexes. More in detail, two novel complexes of silver and gold
The propargylamines are versatile intermediates for the preparation
of various nitrogen-containing compounds and important components
of many biologically active pharmaceutical and natural products, such
as Seleginine and Rasagiline, used to treat symptoms in early
Parkinson's disease and Ladostigil as a neuroprotective agent [4–9].
Propargylamine can be prepared through addition of stoichiometric
quantities of nucleophilic σ-alkyne organometallic reagents (acetylide)
to electrophiles C]N groups (imines or their derivatives). The acet-
ylides are prepared by reaction of terminal alkynes with strong bases
such as alkylmetals, metallized amides, alkoxides or hydroxides [10].
However, these compounds are difficult to manage, and their reactions
must be carried out at low temperatures and under anhydrous condi-
tions. As an alternative to the use of stoichiometric amounts of me-
tallized alkynes, it is possible to carry out this reaction by employing a
catalytic amount of late transition metals. Several metallic compounds
based on iron [11,12], cobalt [13], nickel [14], zinc [15,16], and
mercury [17] showed significant activity in catalyzing this reaction,
bearing
4,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-imida-
zole-2-ylidine ligand (1b and 2b) were synthetized and their catalytic
activity compared with two analogous complexes with hydrogens on
the backbone (1a and 2a), recently synthesized by some of us [24–26]
(Scheme 3).
2. Experimental part
2.1. Materials and methods
All reactions involving organometallic compounds were performed
under an oxygen- and moisture-free atmosphere using standard Schlenk
and glovebox techniques. All solvents were thoroughly deoxygenated
⁎
Corresponding author at: Department of Science (DIS), University of Basilicata, Campus Macchia Romana, Viale Dell’Ateneo Lucano 10, 85100, Potenza, Italy.
E-mail address: annaluisa.mariconda@unibas.it (A. Mariconda).
https://doi.org/10.1016/j.mcat.2019.110570
Received 11 June 2019; Received in revised form 31 July 2019; Accepted 19 August 2019
2468-8231/ © 2019 Elsevier B.V. All rights reserved.

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
Scheme 1. The A3 reaction for the synthesis of propargylamines.
were calibrated externally using a mix of peptide clusters in MALDI
ionization positive ion mode. A linear calibration was applied. To im-
prove the mass accuracy, the sample spectra were recalibrated intern-
ally by matrix ionization (2,5-dihydroxybenzoic acid).
2
.2. Synthesis of 4,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-
imidazole-2-ylidine
4
,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-imidazole-2-
ylidine was prepared following the strategy proposed by Arnold and co-
workers [27,28], and applying the procedures previously reported by us
[
24,26,29,30].
4
,5-dichloroimidazole (3.00 g, 21.9 mmol) and styrene oxide
3.00 ml, 26.2 mmol) were stirred in 25 ml of CH CN at 80 °C for 12 h.
The reaction mixture was cooled at room temperature and subsequently
(
3
CH I (7 ml, 128 mmol) was added. The mixture was warmed up 80 °C
3
for 8 h. The solvent was concentrated, the salt precipitated and washed
with acetone (2·15 ml). Yield: 55%
Scheme 2. Proposed mechanism for the A3 coupling catalyzed by silver and
1
H NMR (400 MHz, DMSO-d
6
, δ ppm): 9.4
5
(s, 1H, NCHN), 7.4
0
(m,
gold NHC complexes.
5
H, Ph group), 6.0
4
(d, 1H, OH), 4.9
7
(m, 1H, CHOH), 4.4
5
(dd, 1H,
NCH
2
CHOH), 4.3
3
(dd, 1H, NCH
2
CHOH) 3.8
7
(s, 3H, CH ).
3
1
3
and dehydrated under a nitrogen atmosphere by heating at reflux over
suitable drying agents; whereas NMR deuterated solvents (Euriso-Top
products) were kept in the dark over molecular sieves. Reagents were
purchased from Sigma-Aldrich S.r.l. and TCI Chemicals and were used
as received. NMR spectra were recorded on a Bruker AM 300 spectro-
C NMR (75 MHz, DMSO-d , δ ppm): 140.3 (ipso carbon aromatic
6
ring), 137.0 (NCN), 128.8, 128.4, 128.0, 127.2, 125.9 (aromatic car-
bons), 118.9 and 118.6 (NCClCClN), 69.56 (CH CHOH), 54.7 (NCH ),
2
2
35.0 (NCH ).
3
+
ESI-MS (CH CN, m/z): 272.1 [C
3
H
12 13
Cl N O]
2
1
2
H
1
13
meter (300 MHz for H; 75 MHz for C), a Bruker AVANCE 400 spec-
Elemental Analysis: calculated for C
Cl IN O (399.05) C,
2
13
2
2
1
13
trometer (400 MHz for H; 100 MHz for C). NMR samples were pre-
pared by dissolving about 10 mg of compounds in 0.5 ml of deuterated
36.12; H, 3.28; Cl, 17.77; I, 31.80; N, 7.02; O, 4.01. Found C, 36.87; H,
3.11; Cl, 18.02; I, 31.27; N, 6.86; O, 3.90.
1
13
solvent. The H NMR and C NMR chemical shifts are referenced to
SiMe
4
(δ = 0 ppm) by using the residual proton impurities of the
deuterated solvents as internal standards. Multiplicities are abbreviated
as follows: singlet (s), doublet (d), triplet (t), multiplet (m), broad (br)
and overlapped (o). Elemental analyses for C, H, and N were recorded
with a Thermo-Finnigan Flash EA 1112 and were performed according
to standard microanalytical procedures. Chloride and iodide were de-
2.3. Synthesis of silver complex bis-[4,5-dichloro-(N-methy-N’(2-hydroxy-
2-phenyl)ethyl-imidazole-2-ylidene]silver(I)]+[di-iodide-silver] (1b)
−
To a suspension of 4,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)
ethyl-imidazole-2-ylidine (0.500 g, 1.25 mmol) in CH Cl (20 ml) were
2
2
termined indirectly by reaction of AgNO
AgX (X = Cl, I), which was dissolved in Na
the solution was determined by flame atomic absorption spectroscopy
FAAS), and the halogen content was calculated by using the content of
silver.
3
with halogen, precipitation of
added silver oxide (0.174 g, 0.750 mmol) and molecular sieves. The
mixture was stirred for 1.5 h in darkness at room temperature. After
filtration on pad celite, to eliminate AgI byproduct, the solvent was
removed in vacuo. The product was obtained as white solid. Yield: 42%.
2
S
2 3
O
. The silver content in
(
1
H NMR (400 MHz, DMSO-d , δ ppm): 7.3 (m, 5H, Ph group), 5.6
6
9
7
ESI-MS measurements of organic compounds were performed on a
(d, 1H, OH), 5.0 (m, 1H, CHOH), 4.3 (m, 2H, NCH CHOH), 3.8 (s,
3
5
2
5
13
Waters Quattro Micro triple quadrupole mass spectrometer equipped
with an electrospray ion source. ESI-FT-ICR measurements of com-
plexes were performed on a Bruker Solaris XR instrument.
3H, CH ). C NMR (75 MHz, DMSO-d , δ ppm): 181.6 (NCN), 141.4,
3
6
128.3, 127.7, 127.3 125.9 (aromatic carbons), 117.2 and 116.6
(NCClCClN), 71.8 (CH CHOH), 56.9 (NCH ), 37.5 (NCH ).
2
2
3
MALDI-MS: mass spectra were acquired using a Bruker SolariX XR
Fourier transform ion cyclotron resonance mass spectrometer (Bruker
Daltonik GmbH, Bremen, Germany) equipped with a 7 T refrigerated
MALDI-MS
(CH Cl ,
m/z):
555.06 Da
attributable
to
2
2
+
+
[C
1
8
H
18
N OCl ]Ag
4
4
derived from {[(NHC) Ag] -C H
2
6 5
−OH},
+
271.03 Da referable to (NHC) .
actively-shielded
superconducting
magnet
(Bruker
Biospin,
Elemental Analysis: calculated for C H AgCl IN O (777.06) C,
1
2
24
4
4 2
Wissembourg, France). The samples were ionized in positive ion mode
using the MALDI ion source (Bruker Daltonik GmbH, Bremen,
Germany). The mass range was set to m/z 200 – 3000. The laser power
was 28% and 22 laser shots were used for each scan. The mass spectra
37.10; H, 3.11; Ag, 13.88; Cl, 18.25; I, 16.33; N, 7.21; O, 4.12 Found: C,
37.56; H, 3.01; Ag, 13.59; Cl, 18.12; I, 16.24; N, 7.69; O, 3.79.
2

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
3
Scheme 3. Silver and gold complexes utilized as catalysts in A -coupling reactions.
Scheme 4. Synthesis of 4,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-imidazolium-iodide.
Scheme 5. Synthetic scheme for preparation of 1b Ag
complex.
Scheme 6. Synthetic scheme for preparation of 2b Au
complex.
2
.4. Synthesis of gold complex bis-[4,5-dichloro-(N-methy-N’(2-hydroxy-2-
and internal standard (2-bromo mesitylene, 1.00 mmol), were added in
a 10 ml Schlenk tube. The mixture was stirred at 80 °C for 6 h, then it
was cooled to room temperature and diethyl ether/dichloromethane
+
−
phenyl)ethyl-imidazole-2-ylidene]gold(I)] [dichloro-gold] (2b)
,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-imidazole-2-
4
were added. The organic portion was dried over MgSO and filtered,
4
ylidine (0.500 g, 1.25 mmol) and Ag
2
O (0.146 g, 0.629 mmol) were
concentrated and the degree of conversion was calculated by in-
1
dissolved in 20 ml of dichloromethane and stirred for 3 h at room
temperature in darkness. Chloro(dimethylsulfide)gold(I) (0.368 g,
tegrating the H NMR signal at δ 6.89 of the two protons on aromatic
carbons of the internal standard and of protons on the carbon in α to
acetylenic group of propargylamine: at δ 3.43, 2H for N-(3-phenyl-2-
propynyl)piperidine), at δ 3.11, 1H for 1-(1-cyclohexyl-3-phenyl-2-
1
.25 mmol) was added, the mixture was stirred for 6 h at room tem-
perature in darkness and it was filtered on pad celite, the solvent was
removed under reduced pressure. The crude product was washed with
1
propynyl) piperdine), at δ 4.79, H for N-(1,3-diphenyl-2-propynyl)
hexane to give a yellow powder. Yield: 21%
piperidine, respectively.
1
H NMR (400 MHz, DMSO-d
6
, δ ppm): 7.3
3
(m, 5H, Ph group), 5.8
8
N-(3-phenyl-2-propynyl)piperidine.
1
(
br, 1H, OH), 5.1
3
(m, 1H, CHOH), 4.2
3
(m, 2H, NCH CHOH), 3.8 (s,
2
2
H NMR (300 MHz, CD
2
Cl
2
, δ ppm): 7.4
2
(m, 2H, CHAr), 7.3
(t, 4H, NCH CH ), 1.6 (m, 4H,
).
, δ ppm): 131.6, 128.1, 127.3 (3·s, 5C, Car),
0
(m,
3
H, CH
3
).
3H, CHAr), 3.4
NCH CH ), 1.4
3
3
(s, 2H, NCH
(m, 2H, NCH
2
2
), 2.5
3
2
2
0
1
3
C NMR (75 MHz, DMSO-d
6
, δ ppm): 170.7 (NCN), 141.2, 128.4,
2
2
CH CH
2
2
1
3
1
7
27.8, 127.0, 125.7 (aromatic carbons), 117.3 and 116.4 (NCClCClN),
C NMR (75 MHz, CDCl
3
2.0 (CH
2
CHOH), 56.6 (NCH
2
) 37.1 (NCH
3
).
123.5 (s, 1C, Car), 85.1 (s, 1C, C≡C-Ph), 84.9 (s, 1C, C≡C-Ph), 53.3 (s,
MALDI-MS
(CH
2
Cl
2
,
m/z): 739.03 Da
attributable
to
2C, NCH
2
2
CH
2
2
), 48.3 (s, 1C, NCH), 26.1 (s, 2C, NCH
2
CH ), 24.0 (s, 1C,
2
+
[
C
24
H
24
N
4
O
2
Cl
4
]Au
2
NCH CH
CH
).
1
-(1-cyclohexyl-3-phenyl-2-propynyl).
1
H NMR (300 MHz, CD
2
Cl
(d, 1H, NCH), 2.6
(m, 2 H), 1.6 (m, 6 H), 1.5
C NMR (75 MHz, CD Cl , δ ppm): 132.0, 128.8, 128.2 (3·s, 5C,
2
, δ ppm): 7.4
(m, 2 H), 2.3
(m, 2 H), 1.4
2
(m, 2H, CHAr), 7.3 (m,
2
3
2
.5. A -coupling (aldehyde-alkyne-amine) reaction: typical procedure of
3
H, CHAr), 3.1
1
4
3
(m, 2 H), 2.0
(m, 3 H), 1.1
7
(m, 2 H),
(m, 2 H).
3
A -coupling reaction catalyzed by bis NHC-M catalysts
1
.8
6
7
6
3
0
1
3
2
2
Under nitrogen atmosphere, bis-(NHC)-M catalyst (3 mol %), alde-
hyde (1.00 mmol), piperidine (1.2 mmol), phenylacetylene (1.5 mmol)
C
ar), 124.3 (s, 1C, Car), 88.4 (s, 1C, C≡C-Ph), 86.4 (s, 1C, C≡C-Ph),
3

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
Fig. 1. Spectra (A) 1H and (B) 13C NMR of 2b Au complex (starred peaks are due to solvents: dichloromethane and DMSO).
6
4.8 (s, 1C, NCH), 51.2 (s, 2C, NCH
2
CH
2
), 40.1, 31.9, 30.8, 27.3 (4·s,
3. Results and discussion
6
C, Cyclohexyl), 26.6 (s, 2C, NCH
2
CH
2
CH
2
), 25.3 (s, 1C,NCH CH CH ).
2
2
2
N-(1,3-diphenyl-2-propynyl) piperidine.
The complexes, reported in Scheme 3, are light and water stable.
1
H NMR (300 MHz, CD
2
Cl
2
, δ ppm) 7.8
9
, 7.5
(s, 4H, NCH
CH CH ).
7
, 7.5
0
CH
, 7.3
1
, 7.2
4
, 7.1
8
(m,
Hydrolysis tests performed in DMSO/D
2
O (90/10) solution at room
1
(
m, 10H, CHar), 4.7
9
(s, 1H, NCH), 2.5
), 1.4 (m, 2H, NCH
C NMR (75 MHz, CDCl -d
28.0, 127.7, 123.3 (8·s, 12C, Car), 87.5 (s, 1C, C≡C-Ph), 86.1(s, 1C,
CH ), 26.2 (s, 2C,
9
2
2
2
CH
2
), 1.6
2
temperature showed unchanged H NMR spectra after 24 h.
Complexes 1a and 2a were prepared according to ref. [24,26]. The
ligand precursor of complexes 1b and 2b was prepared following the
procedures previously reported by Arnold and co-workers [27,28],
modified by us [25,29,30].
4
H, NCH
2
2
CH CH
2
9
2
2
1
3
3
1
, δ ppm): 138.6, 131.8, 128.5, 128.2,
1
C≡C-Ph), 62.4 (s, 1C, NCH), 50.5 (s, 2C, NCH
2
2
NCH
2
2
CH CH
2
), 24.3 (NCH
2
CH
2
CH ).
2
4

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
3
.1. Synthesis of proligand 4,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)
ethyl-imidazolium-iodide, silver (1b) and gold (2b) complexes
4
,5-dichloro-N-methyl-N’-(2-hydroxy-2-phenyl)ethyl-imidazolium-
iodide was prepared by reaction of i) 4,5-dichloro-imidazole with 1,2-
epoxyethylbenzene, this reaction, by opening of epoxy-ring, leads to the
monoalkylated compound, and ii) addition of CH I produces the imi-
3
dazolium salt in a racemic mixture with 55% of yield (Scheme 4)
[
24–30].
1
13
The structure was confirmed by H and C NMR analysis, with the
proton on cationic carbon showing the characteristic singlet at
1
9
.45 ppm in H NMR spectrum (all attributions are reported in the
Experimental part).
The reaction of the salt with silver oxide (Ag O) produces the cor-
2
responding silver complex (1b, see scheme 5 ), which was characterized
1
13
13
Scheme 7. Solution structures of mono-NHC Ag(I) complexes.
by H and C NMR, mass spectroscopy and elemental analysis.
1
H and C NMR spectra show the predictable signals that were
attributed as reported in the Experimental part. The formation of the
Table 1
1
3
3
complex is confirmed by the diagnostic C NMR sharp resonance of the
carbene carbon at 181.6 ppm. According to elemental analysis, (see
Experimental part) the ratio among ligand, silver and iodide is 1:1:1.
The mass spectrometry spectrum (MALDI-MS, see Fig. S1A) shows more
signals of different intensity around 555.06 Da attributable to
Solvent free synthesis of propargylamines via A -coupling reactions catalyzed
by silver (1a and 1b) and gold (2a and 2b) NHC complexes.
Runa
Catalyst
Aldehyde
Conversion
b
(
%)
+
+
1
2
3
4
5
6
7
8
9
1a
Formaldehyde solution (38%)
Paraformaldehyde
58
13
99
13
96
99
99
83
64
94
99
38
81
99
96
86
[C18H
4
N OCl
]Ag derived from {[(NHC)
Ag] -C
H −OH}. MALDI-
18
4
2
6
5
MS analysis were carried out in order to produce mass spectra with
little fragmentation and mostly singly charged ions, thus facilitating
identification. The multiplicity is due to the two silver and two chlorine
Cyclohexanecarboxaldehyde
Benzaldehyde
2a
1b
2b
Formaldehyde solution
Paraformaldehyde
1
07
109
35
37
isotopes:
Ag and
Ag of abundance nearly equal, and Cl and Cl
Cyclohexanecarboxaldehyde
Benzaldehyde
of abundance 75% and 25%, respectively. According to the reported
characterization, silver complexes 1a and 1b are ionic solids with
Formaldehyde solution
Paraformaldehyde
+
−
[
(NHC)
2
Ag] as a cation and [AgI
2
]
as an anion. It is worth noting
1
1
1
1
1
1
1
0
1
2
3
4
5
6
Cyclohexanecarboxaldehyde
Benzaldehyde
that, in solid-state, a similar silver complex showed an analogous
structure as determined by X-ray diffraction [20].
Formaldehyde solution
Paraformaldehyde
A convenient way to synthesize gold-based metal complexes, by
avoiding difficult workups and strong bases, is to use Ag-NHC as re-
agents for carbene transfer.
Cyclohexanecarboxaldehyde
Benzaldehyde
The complex 2b was synthesized, according to a procedure already
reported [25], by trans-metalation of the situ generated 1b complex
a
Reaction conditions: aldehyde (1.0 mmol), piperidine (1.2 mmol), pheny-
lacetylene (1.5 mmol), bis NHC-M catalyst (3 mol %), 80°C, nitrogen atmo-
with the gold(I)-chloro-(dimethylsulfide) [(Me S)AuCl] at room tem-
2
sphere, 6 h.
perature in darkness (see scheme 6 ).
b
Conversions were determined by 1H NMR analysis, using 2-bromo mesi-
The 2b complex was obtained as white powder, yields: 20%. The
tylene as internal standard.
product was analyzed by NMR, mass spectroscopy and elemental ana-
1
13
lysis. The H and C NMR spectra reported in Fig. 1 show signals at
Table 2
1
70.7 ppm attributable to carbene carbon, at 117.3 and 116.4 ppm for
3
Synthesis of propargylamines via A -coupling reactions catalyzed by silver and
C-Cl unsatured carbons and signal at 72.0 ppm for methine carbon
whose proton appears at 5.13 ppm.
gold NHC complexes in the presence of dioxane as solvent.
Run
a
Catalyst
Aldehyde
Conversion
%)
Also in this case, MALDI-MS data discloses a structure type
(
+
−
[
(NHC)
2
H
Au] [AuCl
2
] , showing signals around 739.03 Da attributable
+
b
b
to [C24
24
4
N O
2
Cl
4
]Au .
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
1a
Formaldehyde solution
Paraformaldehyde
n.d.
n.d.
71
n.d.
65
67
68
22
62
30
99
14
99
71
99
68
Conductivity measurements confirmed the electrolytic nature of
Cyclohexanecarboxaldehyde
Benzaldehyde
both complexes (1b and 2b). In fact, the conductance values, de-
b
termined in CH
2
Cl , showed concentration-dependence on the com-
2
2a
1b
2b
Formaldehyde solution
Paraformaldehyde
pounds (see Tables S1 and S2 of Supplementary Information).
According to these results, it is possible to assume in solution the pre-
sence of an equilibrium among the ionic compound [M
Cyclohexanecarboxaldehyde
Benzaldehyde
Formaldehyde solution
Paraformaldehyde
+
−
(
NHC)
2
] [MX
2
]
[31] and the neutral species M(NHC)X (Scheme 7),
that is usually considered responsible for the catalytic activity of these
Cyclohexanecarboxaldehyde
Benzaldehyde
compounds [31].
Formaldehyde solution
Paraformaldehyde
3
3
.2. Catalytic activity of complexes in A coupling reactions
Cyclohexanecarboxaldehyde
Benzaldehyde
The catalytic behavior of 1a, 1b, 2a and 2b in the synthesis of
3
a
Conversions were determined by 1H NMR analysis, using 2-bromo mesi-
propargylamines, via the A -coupling reactions of aldehyde, amine and
alkyne (Scheme 1), was investigated. A comparison among catalysts
was performed by reacting an aldehyde (i.e.: formaldehyde or paraf-
ormaldehyde or cyclohexyl-aldehyde or benzaldehyde) with piperidine
tylene as internal standard.
b
Not detectable.
5

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
Fig. 2. Minimum energy structures of 1a’, 1b’, 2a’ and 2b’.
Fig. 3. Topographic steric maps of 1a’, 1b’.
The iso-contour curves of steric maps are in Å.
The maps were obtained starting from the
minimum energy structures of complexes opti-
mized by DFT calculations. The complexes are
oriented according to the complex scheme.
Overall %VBur and %VBur representative of
each single quadrant are reported for each
map.
and phenylacetylene, in absence of solvent or using dioxane as solvent.
The results, in solvent-free reaction conditions, are reported in Table 1.
In the experimental part the NMR data of the obtained propargyla-
mines, perfectly coincident with those already reported in the literature
for the same compounds, are detailed, [32,33] and in the Supplemen-
reliability of the data obtained was carried out by isolating the product
3
from run 3. The choice to test our complexes in A -coupling reactions,
using piperidine as amine, and phenylacetylene as alkyne, and chan-
ging only the aldehyde, has been done, in this preliminary work, to
compare our data with the activities on these substrates already re-
ported in literature [34,35].
1
13
tary Information as an example the H and C NMR spectra of product
of run 7 is reported (Fig. S1). In all the runs the conversions were de-
3
All complexes are able to perform A -coupling in screened reactions.
1
termined by H NMR analysis, using as internal standard the 2-bromo
By comparing runs 1–4 with runs 9–12 and runs 5–8 with runs 13–16, it
is possible to observe that silver based catalysts were found to be much
less performing than corresponding gold based compounds.
mesitylene, which has the signals of two protons on aromatic carbons in
an empty area of the spectrum (δ = 6.89). The confirmation of the
6

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
Table 3
backbone (1a’ and 2a’). Indeed, it is not surprising that electron
withdrawing groups on the NHC backbone decrease electron density on
the metal.
Mulliken charge on the metal and bond-dissociation energies (BDE) of NHC and
halogen for 1a’, 1b’, 2a’ and 2b’. Values obtained with DFT calculations using
the PBE0/6–311 G(d,p) basis set.
Mulliken charge
BDE(NHC)a
BDE(halogen)
3
.3.2. BDE analysis
BDE of NHCs for 1b’ and 2b’ are lower than BDE of the corre-
NHC(H)-Ag-I (1a’)
NHC(Cl)-Ag-I (1b’)
NHC(H)-Au-Cl (2a’)
NHC(Cl)-Au-Cl (2b’)
+0.151
+0.158
+0.279
+0.314
55.2
51.3
82.4
78.1
116.0
119.8
142.0
146.2
sponding hydrogen substituted complexes (1a’ and 2a’), indicating a
weaker bond among the metal center and chlorine substituted NHC
ligands (Table 3). In addition, BDE of halogen in trans position with
respect to NHC ligand gives indication on the nature of NHC-metal
bond. More in detail, the higher halogen BDE, shown by complexes
with chlorine substituted NHCs, indicates a weaker σ donation of these
NHC ligands toward the metal.
a
Bond-dissociation energies (BDE) referred to the metal–NHC bond.
Benzaldehyde showed to be the least reactive, whereas cyclohex-
anecarboxaldehyde was completely converted by all catalysts.
Formaldehyde in aqueous solution was moderately reactive in the
presence of silver complexes (run 1 and 9), while good reactivity was
observed with gold-based complexes (run 5 and 13). Finally, paraf-
ormaldehyde showed to be very reactive in the presence of all com-
plexes except 1a.
In summary, according to DFT calculations, higher activity of
chlorine substituted NHC complexes could be attributed to a more
electrophile metal center, possibly able to easily coordinate nucleo-
philes such as alkynes at the very beginning of the catalytic cycle.
It is worth noting that the catalytic systems described in this paper,
especially those gold-based, are among the most active reported in the
literature [45–47].
The high conversions, observed in most of the runs, prevent a full
comprehension of catalytic behavior differences among these com-
plexes. Thus, the same reactions were performed in solution using di-
oxane as solvent, because as already reported in literature, [34,36] due
to the lower concentration of the reagents, the activity in dioxane de-
creases, making any differences more evident. The results are reported
in Table 2.
4
. Conclusions
Silver and gold complexes with N-methyl-N’-(2-hydroxy-2-phenyl)
ethyl substituted NHC ligands, bearing either hydrogen or chlorine at 4
and 5 positions of the imidazolium ring, were synthetized and their
According to results of Table 2, it is possible to depict a trend of
reactivity as 2b > 2a > 1b > 1a, where gold complexes (2a and 2b)
show to be generally more performing than silver ones, and complexes
bearing chlorines on NHC backbone (1b and 2b) are more active than
their analogous with backbone unsubstituted NHC.
3
catalytic activities in A -coupling (aldehyde–alkyne–amine) reactions
3
were compared. A -coupling reactions were conducted by reacting pi-
peridine, phenylacetylene with four different aldehydes: formaldehyde,
paraformaldehyde, cyclohexanecarboxaldehyde and benzaldehyde. All
tested complexes gave complete conversion of cyclohexanecarbox-
aldehyde, while benzaldehyde showed to be the lowest reactive sub-
strate. The catalyst activity was observed to be dependent on the metal
as well as on the NHC backbone substituents. The gold complexes, in
fact, exhibit higher activity than the corresponding silver ones and
chlorine backbone substituents showed to have beneficial effects on
catalysts performances. According to experimental results, it is possible
to report the following trend of reactivity: 2b > 2a > 1b > 1a. To
identify the main reason of the different catalytic behavior, steric and
electronic properties of the supposed active species M(NHC)X were
assessed for the four catalysts by DFT studies. Calculation of the percent
buried volumes and extraction of steric maps showed that no significant
differences can be appreciated for steric properties. On the other hand,
Mulliken analysis disclosed a higher positive density charge for com-
plexes with chlorine NHC substituted backbone (1b’ and 2b’) with re-
spect to the analogous complexes presenting hydrogen substituted
backbone (1a’ and 2a’), and BDE analysis indicates a weaker σ donation
of chlorine substituted NHCs toward the metal.
3.3. DFT analysis
It is generally well accepted in literature, that the active species
involved in the catalytic cycle are of the type M(NHC)X (Scheme 7)
[
31]. Reactivity and stability of NHC-metal complexes are often related
to the steric and electronic properties of the NHC ligands, that can be
fine tuned to optimize the catalytic behavior (see for example refs
[
37–41]). As a consequence, to give a preliminary overview on factors
influencing the catalytic activity of 1a, 1b, 2a and 2b, electronic and
steric properties of NHCs presenting chlorine or hydrogen on the
backbone were investigated by DFT calculations on M(NHC)X species
1
a’, 1b’, 2a’ and 2b’ at the PBE0/6–311 G(d,p) level of theory (see
supporting information for computational details and Cartesian co-
ordinates). Minimum energy structures are reported in Fig. 2.
In order to compare steric parameters of NHC ligands with hydro-
gens or chlorine substituted backbone the percent buried volumes (%
V
Bur) were calculated and steric maps (Fig. 3) were obtained from the
minimum energy structures relative to NHC-Ag-I complexes [42]. %
In this light, the higher activity, observed for chlorine substituted
NHC complexes, could be attributed to a more electrophile metal
center, that possibly promotes the alkyne coordination at the beginning
of the catalytic cycle.
V
Bur is a parameter, able to quantify the steric hindrance of NHC li-
gands, defined as the fraction of the total volume of a sphere centered
on the metal occupied by a given ligand [43,44]. Both NHCs present %
V
Bur = 30.4 and anisotropic hindrance that is more pronounced in the
SE quadrant of the steric maps due to the presence of the phenyl group
oriented toward the catalytic task. No meaningful differences could be
appreciated among the chlorine substituted and hydrogen substituted
NHCs.
Acknowledgments
The authors are grateful to Dr. Patrizia Oliva and Dr. Patrizia
Iannece for the technical assistance. Financial support from the
Ministero dell’Università e della Ricerca Scientifica e Tecnologica is
gratefully acknowledged.
Electronic properties were assessed by Mulliken charge and BDE
analysis.
3
.3.1. Mulliken analysis
According to Mulliken charges on the metal reported in Table 3, a
Appendix A. Supplementary data
more pronounced positive density charge were calculated for com-
plexes with chlorine NHC substituted backbone (1b’ and 2b’) with re-
spect to the analogous complexes presenting hydrogen substituted
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2019.110570.
7

A. Mariconda, et al.
Molecular Catalysis 480 (2020) 110570
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